Cirrhosis

Japanese: 肝硬変

Definition and Concept: Cirrhosis is the final stage of chronic liver damage caused by a variety of etiologies (Table 9-5-1), and is defined as a pathological condition in which hepatocytes are replaced by fibers, the original hepatic lobules are remodeled, and pseudolobules are formed. Regardless of the cause of cirrhosis, degeneration and necrosis of hepatocytes occurs, and if this continues for a long period of time, collagen fiber proliferation and nodular regeneration of hepatocytes are observed, causing the liver surface to become uneven.
Classification
1) Morphological classification:
In Japan, Nagayo's Classification of Type A and Type B and Miyake's Classification of Type A, Type B, Type B, and Type F have been used. Recently, the WHO classification has classified regenerative nodules (pseudolobules) into three types based on their size: micronodular type, macronodular type, and mixed nodular type, in which small and large regenerative nodules are almost equally mixed.
2) Functional classification:
This is a clinical classification, and is divided into two categories: compensated and decompensated. In compensated cirrhosis, the disease has progressed to the stage of cirrhosis, but liver reserve function is relatively well-maintained, and in most cases does not interfere with daily life.
In decompensated cirrhosis, liver damage progresses and liver reserve declines, causing symptoms of liver failure such as jaundice, ascites, and hepatic encephalopathy, which interfere with daily life. The Child-Pugh score (Table 9-5-2), which combines clinical findings and liver function tests, has long been used widely to classify the severity of cirrhosis.
Epidemiology: It is estimated that there are approximately 400,000 to 500,000 patients with cirrhosis in Japan, with a male-to-female ratio of approximately 2:1. The number of deaths from liver disease, excluding deaths from primary liver cancer (32,765 people per year), is 16,216, the majority of which are thought to be due to cirrhosis (Ministry of Health, Labour and Welfare, 2010 Vital Statistics). Hepatocellular carcinoma is the cause of death in 70-80% of patients with cirrhosis, followed by liver failure and gastrointestinal bleeding.
The most common cause of cirrhosis is hepatitis C virus infection, followed by hepatitis B virus infection and cirrhosis due to heavy alcohol consumption, which account for roughly equal numbers of cases (Figure 9-5-1). In recent years, it has become clear that cases of cirrhosis of unknown cause include the terminal stage of non-alcoholic steatohepatitis, and it has been noted that the number is increasing year by year.
Pathophysiology Blood flow in the liver passes through the sinusoids from the capsule of Glisson toward the central vein (Figure 9-5-2). Sinusoids are formed around endothelial cells with small pores (fenestra), and are composed of hepatic stellate cells (also called Ito cells) that surround the outside of the sinusoids and support their structure, and immune-related cells such as Kupffer cells and Pit cells that are present in the sinusoidal blood and adhere to the sinusoidal endothelium. The space between the endothelial cells and hepatocytes is called the space of Disse, and in normal liver, low concentrations of extracellular matrix such as type IV collagen, fibronectin, laminin, and proteoglycan are present, but a major characteristic is that no clear basement membrane is formed. Liver fibrosis in cirrhosis is a pathology that follows necrosis of hepatocytes, and the hepatic stellate cells (also called Ito cells) present in the space of Disse play the most important role in liver fibrosis. Normal liver stores a large amount of vitamin A, but activated hepatic stellate cells due to liver injury are transformed into myofibroblast-like cells and produce excess extracellular matrix such as collagen type I and type III, proteoglycan, fibronectin, and hyaluronic acid. Activated hepatic stellate cells produce matrix-degrading enzymes (matrix metalloproteinases: MMPs) and their inhibitors, tissue inhibitors of matrix metalloproteinases (TIMPs), and are involved in both the production and degradation of extracellular matrix. In chronic liver injury, fibrosis exceeds fibrosis, and excessive deposition of fibers in the Disse space leads to the disappearance of endothelial cell pores and basement membrane-like changes, sinusoids become capillary, blood flow is impaired, and the hepatic lobule structure is destroyed, leading to blood flow abnormalities such as the formation of intrahepatic shunts and collateral circulation (extrahepatic shunts).
Clinical symptoms Clinical symptoms due to liver cirrhosis can be broadly divided into those due to hepatocellular dysfunction (mainly caused by a decrease in the number of functional hepatocytes) and those due to portal hypertension (compression of intrahepatic hepatic venous branches by regenerative nodules, and formation of intrahepatic and extrahepatic shunts due to capillaryization of sinusoids) (Table 9-5-3).
1) Symptoms:
Many patients are asymptomatic during the compensated stage, but non-specific symptoms include general fatigue, easy fatigue, abdominal distension, loss of appetite, decreased libido, and slight fever. Patients may also complain of abnormalities in taste and smell, and cramps. The frequency of such subjective symptoms increases particularly during the decompensated stage.
2) Objective symptoms:
Objective symptoms also vary, particularly in the decompensated stage. The skin appears dark brown, and as the disease progresses, jaundice appears, with the conjunctiva and skin becoming yellowish. The patient also enters a state of protein energy malnutrition (PEM), with a decrease in subcutaneous fat and skeletal muscle mass due to nutritional deficiencies. Pancytopenia appears with increased splenic function, and internal hemorrhagic spots may be seen on the skin due to mild anemia and a tendency to bleed.
In patients with cirrhosis, due to impaired breakdown of the female hormone estrogen, gynecomastia, testicular atrophy, and dilated skin capillaries may occur in men. Vascular spider angiomas may appear on the neck, precordium, and upper arms, and palmar erythema may appear on the soft parts of the palms, such as the thenar and hypothenar eminences, and the bases of the fingers.
Other symptoms that may be observed include clubbing, white nails, parotid gland swelling (alcoholic cirrhosis), and Dupuytren's contracture (alcoholic cirrhosis).
Ascites is observed in advanced stages of the disease due to factors such as portal hypertension, accelerated reabsorption and retention of sodium and water in the kidneys, and reduced plasma oncotic pressure due to hypoalbuminemia (reduced albumin production) caused by decreased liver function exacerbates this symptom. Peripheral edema and pleural effusion (often on the right side) may also appear. Ascites accumulation results in abdominal distension and a palpable fluctuating abdominal wall. It may also lead to abdominal wall hernia or umbilical hernia.
Portal hypertension causes the anastomotic veins between the portal vein and the caval system to develop as collateral circulation for portal blood, resulting in the formation of engorged abdominal wall veins (caput medusae) that develop around the navel. Esophageal and gastric varices also form, and their rupture can cause hematemesis and bloody stool. The formation of portal-systemic shunts and impaired liver function increases the blood concentration of neurotoxic substances such as ammonia. Patients may experience changes in sleep rhythm, personality changes, and abnormal behavior, as well as flapping tremor (neurologically), and hepatic encephalopathy (hepatic coma in severe cases). Abdominal findings include atrophy of the right lobe of the liver in advanced cirrhosis, and a hard, swollen left lobe of the liver can be palpated in the epigastric region. However, in cases of alcoholic cirrhosis, a greatly swollen right lobe of the liver is often palpated. An enlarged spleen may also be palpated, reflecting portal hypertension.
Test results
1) Blood test:
Depending on the degree of hypersplenism, pancytopenia (thrombocytopenia, leukopenia, anemia) may occur.
Biochemical tests show decreased hepatic synthetic ability (decreased serum albumin, total cholesterol, cholinesterase, prolonged prothrombin time), increased serum total bilirubin (in the terminal stage, indirect bilirubin becomes predominant due to decreased conjugation ability), fluctuations in serum transaminase (ALT, AST) values (in advanced cases, values may be within the normal range due to a decrease in remaining hepatocytes), decreased hepatic reticuloendothelial function, elevated gamma globulin reflecting a decreased ability to remove antigens such as endotoxin derived from the intestine due to portal-systemic shunting, and enhanced colloidal reaction (elevated TTT, ZTT). Biliary enzymes (ALP, γ-GTP) also show mild elevations, but may show high values, especially in alcoholic cirrhosis.
Furthermore, there is an increase in ammonia, an increase in aromatic amino acids (AAA) and a decrease in branched chain amino acids (BCAA), resulting in a decrease in the Fischer ratio (branched chain amino acids/aromatic amino acids). Recently, the BTR (total branched chain amino acids/tyrosine molar ratio), which measures only the aromatic amino acid tyrosine, has come to be commonly used as a substitute for the Fischer ratio.
In patients with cirrhosis, impaired glucose tolerance (hyperinsulinemia and persistent postprandial hyperglycemia) and insulin resistance are observed in approximately 70% of cases, but fasting blood glucose and HbA1c (which show low values due to hypersplenic function and shortened red blood cell lifespan) are often within the normal range, so caution is required.
Elevations in fibrosis markers such as type IV collagen, hyaluronic acid, and type III procollagen peptide (PIIIP) are helpful in making the diagnosis.
2) Imaging tests:
Abdominal ultrasound, CT (Figure 9-5-3), and MRI show liver deformation (often atrophy of the right hepatic lobe and hypertrophy of the lateral liver segment and caudate lobe), blunting of the liver margin, irregularities in the liver surface, and irregularities in the liver parenchyma. As the disease progresses, narrowing of the intrahepatic vascular system, splenomegaly, dilation of the main portal vein, ascites, and development of collateral circulation (left gastric vein, paraumbilical vein, splenic vein, etc.) are also seen. Liver scintigraphy using ^99mTc fluoride, which examines uptake into the reticuloendothelial system, shows a flying bat image, but this is rarely performed these days.
Diagnosis Definitive diagnosis is made pathologically and morphologically by laparoscopy (Figure 9-5-3) or liver biopsy (Figure 9-5-4). However, these tests are invasive and may not be performed due to bleeding tendency. Therefore, in daily clinical practice, diagnosis is made comprehensively from physical findings, blood tests, and imaging test findings, but it may be difficult to differentiate from chronic hepatitis. In recent years, ultrasound-based liver stiffness measurement devices have been applied clinically, making it possible to perform non-invasive liver fibrosis diagnosis with a high degree of accuracy, and correlation with pathological tissue images has been obtained to a certain extent. It is thought that non-invasive diagnosis of liver cirrhosis will become possible if equipment is improved and clinical research progresses in the future. On the other hand, it is important to search for complications of liver cirrhosis. The presence of esophageal and gastric varices by upper gastrointestinal endoscopy is a finding of portal hypertension associated with liver cirrhosis, and is an indirect diagnosis of liver cirrhosis. In addition, since the presence or absence of hepatocellular carcinoma is directly related to prognosis, early diagnosis is necessary, and a combination of tumor markers and various imaging diagnostics is performed.
complications
1) Gastrointestinal bleeding:
In addition to rupture of esophageal and gastric varices, bleeding from gastric and duodenal ulcers and gastric erosions is also common. Most cases of massive bleeding are due to rupture of esophageal and gastric varices, but bleeding from rectal varices can also occur in rare cases.
In the event of bleeding, an infusion route is established, and after vital signs have stabilized, emergency endoscopy is performed, if deemed feasible, to identify the source of bleeding and attempt hemostasis. For bleeding from esophageal varices, endoscopic injection sclerotherapy (EIS) or endoscopic variceal ligation (EVL) is performed. For bleeding from gastric varices, sclerotherapy using tissue adhesive is performed, followed by elective balloon-occuluded retrograde transvenous obliteration (BRTO) via a gastrorenal shunt. If such emergency hemostasis cannot be performed, a Sengstaken-Blakemore tube is inserted through the nose, pressure is applied to stop the bleeding, and the patient is transported to a specialized facility. In cases of repeated bleeding from varices, a transjugular intrahepatic portosystemic shunt (TIPS) may be attempted to reduce portal vein pressure. For varicose veins that are at risk of bleeding, EIS or EVL and BRTO are performed prophylactically.
2) Hepatic encephalopathy:
Hepatic encephalopathy is caused by hepatocellular dysfunction and the formation of a portal-systemic shunt, and is often triggered by constipation, gastrointestinal bleeding, infection, dehydration, or the use of psychotropic drugs. Patients may experience psychiatric symptoms such as day-night reversal, impaired memory, delirium, abnormal behavior, drowsiness, and coma, as well as flapping tremors. When hepatic encephalopathy develops, an enema is administered using 10-30% lactulose solution diluted with lukewarm water, and an intravenous drip of a specially formulated amino acid preparation is administered. When hepatic encephalopathy develops, protein intake is temporarily restricted to 0.5-0.7 g/kg, but extreme long-term protein restriction can promote malnutrition, so protein restriction should only be limited to the acute phase of hepatic encephalopathy. To kill ammonia-producing bacteria and prevent endotoxemia, poorly absorbed antibiotics such as kanamycin may also be administered orally.
3) Ascites:
The general rule is to keep the patient in bed, restrict fluid intake (less than 1L per day), and strictly restrict salt intake (3-5g). If these treatments are ineffective, drug therapy is used. Diuretics should be started with an antialdosterone drug, which is a potassium-sparing diuretic, and if this is insufficient, a loop diuretic should be added. To increase serum albumin, oral nutritional supplements for liver failure should also be considered. Patients with severe hypoalbuminemia (less than 2.5g/dL) are less responsive to diuretics, and albumin preparations should be administered. For refractory ascites that does not respond to these treatments (refractory ascites), ascites paracentesis, concentrated ascites reinfusion therapy, transjugular intrahepatic portosystemic shunt (TIPS), or peritoneovenous shunt (Denver shunt) may be used.
4) Spontaneous bacterial peritonitis (SBP):
In patients with liver cirrhosis, bacterial translocation is likely to occur in the intestine, and hematogenous infection with bacteria originating from the intestine is likely to occur due to decreased reticuloendothelial function, decreased opsonic activity, and the formation of portal-systemic shunts. SBP is suspected in patients with ascites who have fever and abdominal pain, and an ascites paracentesis test is performed. It is diagnosed based on the presence of bacteria in the ascites and an increase in the number of polymorphonuclear leukocytes in the ascites. Even if bacterial culture is negative, SBP can be diagnosed if the neutrophil count in the ascites is 500/μL or higher, or if the neutrophil count is 250-500/μL and is accompanied by subjective and objective symptoms. It is often caused by gram-negative bacilli.
5) Coagulation disorders:
In cirrhosis, in addition to thrombocytopenia caused by hypersplenism, decreased synthesis of coagulation factors in the liver leads to decreased synthesis of fibrinogen (factor I), prothrombin (factor II), factors V, VI, IX, and X. The combination of cholestasis can cause impaired absorption of fat-soluble vitamin K, further decreasing each factor except factor V.
6) Hepatorenal syndrome:
This is acute renal failure seen in patients with end-stage liver failure due to cirrhosis. Changes in blood flow within the kidney cause spasm of blood vessels in the renal cortex, reducing renal blood flow and glomerular filtration rate. It is triggered by intravascular dehydration due to excessive administration of diuretics, removal of ascites by abdominal paracentesis, diarrhea, etc.
It is divided into type I, which progresses rapidly, and type II, which progresses relatively slowly and is accompanied by refractory ascites.
7) Hepatocellular carcinoma:
【⇨9-12-1）】
Course and prognosisThe course and prognosis of liver cirrhosis vary depending on the cause. The three leading causes of death from liver cirrhosis are liver failure, gastrointestinal bleeding, and hepatocellular carcinoma. However, the proportion of deaths due to hepatocellular carcinoma is increasing, and the complication of hepatocellular carcinoma has become a factor that determines prognosis. This is thought to be due to advances in treatment for liver failure and gastrointestinal bleeding.
The Child-Pugh score is a method for evaluating hepatic reserve function, but is also useful for predicting prognosis; patients with grade C have an extremely poor prognosis. In addition, the model for end stage liver disease (MELD) score is calculated using serum bilirubin, creatinine, and prothrombin time as a short-term prognostic predictor, and is useful for predicting prognosis before liver transplantation and determining suitability for liver transplantation. *Evaluation for liver transplantation (MELD score) MELD score = 3.78 x log _e (T-Bil mg/dL) + 11.2 x log _e (PT-INR) + 9.57 x log _e (Cre mg/dL) + 6.43
Treatment
1) Guidance on daily life:
In the decompensated stage, when jaundice, ascites, and hepatic encephalopathy are present, patients should rest. In the compensated stage, when liver function is stable and there are no esophageal varices at risk of rupture, excessive rest should be avoided in order to prevent muscle atrophy; rather, it is advisable to engage in light exercise (to the extent that the patient does not feel fatigued).
2) Drug therapy:
Efforts should be made to suppress liver inflammation and maintain liver function using liver protective agents such as ursodeoxycholic acid and glycyrrhizin preparations, and iron depletion therapy (if no anemia is present). For patients with serum albumin levels below 3.5 g/dL, administration of branched-chain amino acid preparations should be considered.
As a causal treatment, in cases of cirrhosis caused by the hepatitis B virus, antiviral drugs (nucleoside analogues) are administered to improve the liver pathology and prevent progression to decompensated cirrhosis. In cases of compensated cirrhosis caused by the hepatitis C virus, if the hepatitis C virus can be eliminated through interferon treatment (either alone or in combination with ribavirin), it is expected that the pathology will improve and the development of liver cancer will be prevented.
3) Diet and nutritional therapy:
The diet should be balanced, low in salt and high in dietary fiber.
Calorie intake is calculated from the intensity of daily activity. In compensated cirrhosis, the recommended intake is 25-35 kcal/kg (standard body weight)/day, protein 1.0-1.3 g/kg (standard body weight)/day, and lipid intake should be 20-25% of total energy. Patients with cirrhosis are in a state of starvation when hungry early in the morning, which can cause a deterioration in their nutritional status, so they should eat a late evening snack (LES) before going to bed in separate meals. Approximately 200 kcal should be subtracted from the total daily calorie intake and an oral nutritional supplement for liver failure (approximately 200 kcal) rich in branched-chain amino acids should be taken before going to bed. In addition, patients should be advised to abstain from alcohol, which is a factor that aggravates cirrhosis. Patients with cirrhosis should be advised to refrain from eating raw foods (especially sashimi in the summer) because their immune function is weakened. This is because a type of Vibrio bacteria called Vibrio vulnificus grows in seafood as seawater temperatures rise; if a healthy person eats food contaminated with this bacteria, they will only experience diarrhea; however, if a patient with cirrhosis becomes infected with this Vibrio bacteria, the condition can become serious and potentially life-threatening.
4) Ascites: See Complications
5) Hepatic encephalopathy: See Complications
6) Gastrointestinal bleeding: see Complications
7) Liver transplantation:
In cases of decompensated cirrhosis with progressive jaundice, liver transplantation is considered. In Japan, the number of deceased donor liver transplants is still low, and living donor liver transplants are currently the mainstream. The appropriate time for liver transplantation is determined by objective indicators such as the MELD score and clinical evaluation. [Sakaiida Isao]
■ References
Sherlock S, Dooley J; translation supervised by Omata Masao: Sherlock Hepatology. pp315-328, Nishimura Shoten, Tokyo, 2004.

Table 9-5-1
Causes of liver cirrhosis

Table 9-5-1

Table 9-5-2
Child-Pugh score ">

Table 9-5-2

Table 9-5-3
Symptoms and Signs of Liver Cirrhosis

Table 9-5-3

Figure 9-5-1
Nationwide incidence of liver cirrhosis by cause

Figure 9-5-1

Figure 9-5-2
Structure of the hepatic sinusoids

Figure 9-5-2

Source : Internal Medicine, 10th Edition About Internal Medicine, 10th Edition Information

Japanese:

定義・概念
　肝硬変とは，さまざまな病因（表9-5-1）で生じた慢性肝障害の終末像であり，肝細胞が線維で置換され，本来の肝小葉は改築され，偽小葉が形成された病態として定義される．肝硬変はその原因にかかわらず，肝細胞の変性・壊死が生じ長期にそれが持続すると，膠原線維の増生と肝細胞の結節性再生が認められ肝表面は凹凸を呈するようになる．
分類
1）形態学的分類：
わが国では，長与の甲乙分類，三宅の甲甲′ 乙乙′F型分類が用いられてきた．最近ではWHO分類として再生結節（偽小葉）の大きさにより，小結節型（micronodular type），大結節型（macronodular type），小結節と大結節の再生結節がほぼ均等に混在する混合型（mixed nodular type）の3型に分類している．
2）機能的分類：
臨床的に用いられる分類であり，代償性（compensated）と非代償性（decompensated）の2つに分類される．代償性肝硬変は，肝硬変にまで病期は進行しているが，肝予備能が比較的保たれている状態で，多くの場合日常生活に支障をきたさない状態である．
　非代償性肝硬変では，さらに肝障害が進行し肝予備能の低下により，黄疸，腹水，肝性脳症などの肝不全症状が出現し，日常生活に支障をきたす状態である．肝硬変の重症度分類としては，臨床所見と肝機能検査を組み合わせたChild-Pughスコア（表9-5-2）が古くから広く用いられている．
疫学
　わが国の肝硬変患者は約40万～50万人，男女比は約2：1と推定されている．原発性肝癌による死亡（年間32765人）を除く肝疾患死亡者数は16216人であり，その大半が肝硬変による死亡と考えられる（厚生労働省平成22年人口動態統計）．肝硬変患者の死因は70～80％が肝細胞癌によるものであり，続いて肝不全，消化管出血となる．
　肝硬変の成因で最も多いのは，C型肝炎ウイルス感染であり，ついでB型肝炎ウイルス感染とアルコール多飲による肝硬変はほぼ同数を占めている（図9-5-1）．近年，原因不明の肝硬変のなかに非アルコール性脂肪肝炎（non-alcoholic steatohepatitis）の終末像が含まれることが明らかとなっており年々増加傾向にあることが指摘されている．
病態生理
　肝蔵内の血流は，Glisson鞘から中心静脈に向かって，類洞を通過する（図9-5-2）．　類洞は，小孔（fenestra）のある内皮細胞を中心に形成され，類洞の外側を取り囲みその構造の下支えをしている肝星細胞（hepatic stellate cell，伊東細胞ともよぶ）と類洞血中に存在し類洞内皮に接着しているKupffer細胞やPit細胞などの免疫に関与する細胞などで構成されている．内皮細胞と肝細胞の間の空間をDisse腔とよぶが，正常肝では，Ⅳ型コラーゲン，フィブロネクチン，ラミニン，プロテオグリカンなどの細胞外マトリックスが低濃度に存在するが，明らかな基底膜を形成していないのが大きな特徴である．肝硬変における肝線維化は，肝細胞の壊死後に続く病態であり，肝線維化に最も重要な働きをしているのは，Disse腔に存在する肝星細胞（伊東細胞ともよばれている）である．正常肝では大量のビタミンAを貯蔵しているが，肝障害により活性化された肝星細胞は形質転換し筋線維芽細胞様に変化し，Ⅰ型，Ⅲ型コラーゲン，プロテオグリカン，フィブロネクチン，ヒアルロン酸などの細胞外マトリックスを過剰に産生する．活性化肝星細胞は，マトリックス分解酵素（matrix metalloproteinase：MMP）とその阻害物質であるtissue inhibitor of matrix metalloproteinase（TIMP）を産生し，細胞外マトリックスの産生と分解の両方にかかわっている．慢性肝障害では，線維産生が線維分解を上回る状態となり，Disse腔に線維が過剰に沈着すると，内皮細胞の小孔は消失して基底膜様変化を起こし，類洞は毛細血管化して血流障害が生じ，肝小葉構造が破壊され，肝内短絡絡（肝内シャント）の形成，側副血行路（肝外短絡路）の形成などの血流異常をひきおこす．
臨床症状
　肝硬変による臨床症状は，肝細胞機能不全によるもの（機能的肝細胞数の減少が主因）と，門脈圧亢進によるもの（再生結節による肝内肝静脈枝の圧迫，類洞の毛細血管化などによる肝内外の短絡形成）に大別される（表9-5-3）．
1）自覚症状：
代償期には無症状例が多いが，非特異的症状として，全身倦怠感，易疲労感，腹部膨満感，食欲不振，性欲減退，微熱などがある．味覚，嗅覚の異常やこむら返りを訴えることもある．特に非代償期になるとこのような自覚症状の頻度が増加する．
2）他覚症状：
他覚症状も特に非代償期になるとさまざまな所見を呈するようになる．皮膚は暗褐色調を呈し，病期の進行とともに黄疸が出現し，眼球結膜および皮膚の黄染を認める．また，蛋白質・エネルギー低栄養状態（protein energy malnutrition：PEM）となり，栄養障害による皮下脂肪，骨格筋量の減少がみられる．脾機能亢進とともに汎血球減少が出現し，軽度の貧血，出血傾向のため皮膚に内出血斑を認めることがある．
　肝硬変患者では女性ホルモンであるエストロゲンの分解障害により，男性での女性化乳房，睾丸萎縮や皮膚毛細血管の拡張がみられ，頸部，前胸部，上腕にかけてくも状血管腫（vascular spider），母指球，小指球，指の付け根などの手掌のやわらかい部分には手掌紅斑（palmar erythema）が出現することがある．
　その他，ばち指，白色爪，耳下腺腫脹（アルコール性肝硬変），Dupuytren拘縮（アルコール性肝硬変）などを認めることがある．
　腹水は，門脈圧亢進症，腎でのナトリウムと水分の再吸収促進，貯留などの因子により病期の進行した状態で認められ，肝機能低下による低アルブミン血症（アルブミン産生低下）による血漿膠質浸透圧低下がこの症状を助長させる．末梢の浮腫や胸水（多くの場合右側）の出現もある．腹水貯留の結果，腹部膨満がみられ，腹壁の波動を触知する．また，腹壁ヘルニア，臍ヘルニアに至ることもある．
　門脈圧亢進症により，門脈系と大静脈系の吻合静脈が門脈血の側副血行路として発達する結果，臍を中心に発達した腹壁静脈の怒張（メズサの頭）が形成される．また，食道胃静脈瘤が形成され，破裂により，吐血・下血がみられる．門脈-大循環短絡路（シャント）の形成や肝機能低下により，アンモニアなどの神経毒性物質の血中濃度が増加する．睡眠リズムの変化，性格変化，さらには異常行動，神経学的には羽ばたき振戦（flapping tremor）がみられ，肝性脳症（重症例では肝性昏睡）を生じる．腹部所見としては，進行した肝硬変では肝右葉は萎縮しており，硬く腫大した肝左葉を心窩部に触知する．ただし，アルコール性肝硬変の場合は大きく腫大した肝右葉を触知することが多い．門脈圧亢進を反映し腫大した脾臓を触知することもある．
検査成績
1）血液検査：
脾機能亢進症の程度により汎血球減少（血小板減少，白血球減少，貧血）を認める．
　生化学検査では，肝合成能の低下（血清アルブミン，総コレステロール，コリンエステラーゼの低下，プロトロンビン時間の延長），血清総ビリルビン値の増加（末期では，抱合能低下により，間接型が優位となる），血清トランスアミナーゼ（ALT，AST）値の変動（進行例では残存肝細胞減少により正常範囲のこともある），肝における網内系機能低下，門脈-大循環短絡路による腸管由来のエンドトキシンなどの抗原の除去能低下を反映したガンマグロブリン上昇，膠質反応亢進（TTT，ZTTの上昇）がみられる．胆道系酵素（ALP，γ-GTP）も軽度上昇を示すが，特にアルコール性肝硬変では高値を示すことがある．
　さらに，アンモニア上昇や芳香族アミノ酸（aromatic amino acid：AAA）の上昇と分岐鎖アミノ酸（branched chain amino acid：BCAA）の低下が起こり，Fischer比（分岐鎖アミノ酸/芳香族アミノ酸）は低下する．最近では芳香族アミノ酸のチロシンだけを測定するBTR（総分岐鎖アミノ酸/チロシンモル比）が，Fischer比の代用として汎用されている．
　肝硬変では，耐糖能異常（高インスリン血症と食後の持続する高血糖）ならびにインスリン抵抗性を70％前後に認めるが，空腹時血糖やHbA1c（脾機能亢進で赤血球寿命の短縮のため低値を示す）は正常範囲であることも多く，注意が必要である．
　線維化マーカーであるⅣ型コラーゲン，ヒアルロン酸，Ⅲ型プロコラーゲンペプチド（PⅢP）の上昇は診断の参考となる．
2）画像検査：
腹部超音波検査，CT（図9-5-3），MRIで，肝臓の変形（多くは肝右葉の萎縮と肝外側区域と尾状葉の肥大），肝辺縁の鈍化，肝表面の不整凹凸，肝実質の不整像を認める．また病態の進行により肝内脈管系の狭小化，脾腫大，門脈本幹の拡張，腹水，側副血行路（左胃静脈，臍傍静脈，脾静脈など）の発達を認める．網内系への取り込みをみる^99mTcフチン酸を用いた肝シンチグラフィではflying bat像を呈するが，最近ではほとんど行われることはない．
診断
　確定診断は，腹腔鏡検査（図9-5-3）や肝生検（図9-5-4）により，病理・形態学的に行われる．しかし，これらの検査は侵襲的であり，出血傾向のため施行できない場合もある．そのため，日常診療での診断は，身体所見，血液検査，画像検査所見から総合的に判断するが，慢性肝炎との鑑別が困難な場合もある．近年，超音波を用いた肝硬度測定機器が臨床応用され，非侵襲的に肝線維化診断がかなり正確に行えるようになり，病理組織像との相関もある程度まで得られ，今後機器改良と臨床研究が進めば，非侵襲的な肝硬変の診断も可能になると考えられる．他方，肝硬変の合併症の検索は重要である．上部消化管内視鏡検査による食道胃静脈瘤の存在は，肝硬変に伴う門脈圧亢進症の所見であり，間接的な肝硬変診断となる．また肝細胞癌の有無は予後に直結することから，早期診断が必要であり，腫瘍マーカーや各種画像診断を組み合わせた検索を行う．
合併症
1）消化管出血：
食道・胃静脈瘤の破裂のほか，胃十二指腸潰瘍，胃びらんからの出血の頻度も高い．大量出血の多くは食道胃静脈瘤破裂によるが，まれに直腸静脈瘤からの出血もみられる．
　出血時には，輸液ルートを確保し，バイタルサインが安定したのちに，実施可能と判断した場合は，緊急内視鏡検査を施行し出血源の確認と止血を試みる．食道静脈瘤からの出血に対しては内視鏡的硬化療法（endoscopic injection sclerotherapy：EIS）あるいは内視鏡的静脈瘤結紮術（endoscopic variceal ligation：EVL）が行われる．胃静脈瘤からの出血では組織接着剤を用いた硬化療法を行い，その後，待機的に胃腎短絡路を介してバルーン下逆行性経静脈的塞栓術（balloon-occuluded retrograde transvenous obliteration：BRTO）が行われることが多い．このような緊急止血法が施行できない場合Sengstaken-Blakemoreチューブを経鼻挿入し，圧迫止血を行い専門施設に搬送する．静脈瘤からの出血を繰り返す症例では門脈圧低下をめざし経頸静脈的肝内門脈大循環短絡術（transjugular intrahepatic portosystemic shunt：TIPS）が試みられることもある．　出血の危険性のある静脈瘤に対しては，予防的に，EISあるいはEVLならびにBRTOが行われている．
2）肝性脳症：
肝性脳症は，肝細胞機能不全と門脈-大循環短絡路形成（シャント形成）により生じ，便秘，消化管出血，感染，脱水，向精神病薬服用などが契機になり生じることが多い．昼夜逆転，記銘力低下，譫妄，異常行動，傾眠傾向，昏睡などの精神症状や羽ばたき振戦がみられる．肝性脳症の発症時には微温湯で希釈した10～30％のラクツロース液による浣腸を行い，特殊組成アミノ酸製剤の点滴を行う．肝性脳症発症時には，蛋白摂取は一時的に0.5～0.7g/kgに制限するが，長期間の極端な蛋白制限は栄養不良を助長するため，蛋白制限は肝性脳症の急性期に限る．アンモニア産生性細菌の殺菌やエンドトキシン血症の予防目的に，カナマイシンなどの難吸収性抗生物質の経口投与の併用を行うこともある．
3）腹水：
安静臥床，水分制限（1日1L以下），厳重な塩分制限（3～5 g）が原則である．これら治療に無効の場合は薬物治療を行う．利尿薬は，K保持性利尿薬である抗アルドステロン薬から開始し，効果が不十分な場合は，ループ利尿薬を追加する．血清アルブミンを増加させるため，肝不全用経口栄養剤の投与も考慮する．低アルブミン血症が高度（2.5 g/dL以下）の場合は利尿薬への反応性が乏しいため，アルブミン製剤を投与の対象となる．これらの治療に反応しない治療抵抗性の腹水（難治性腹水）に対しては，腹水穿刺排液，腹水濃縮再注入療法，経頸静脈的肝内門脈大循環短絡術（transjugular intrahepatic portosystemic shunt：TIPS）や腹腔-静脈シャント（Denver shunt）が行われることがある．
4）特発性細菌性腹膜炎（spontaneous bacterial peritonitis：SBP）：
肝硬変では，腸管におけるbacterial translocationが生じやすく，網内系機能の低下，オプソニン活性の低下，門脈-大循環シャント形成により腸管由来の細菌の血行性感染が生じやすい．発熱，腹痛を認める腹水患者は，SBPを疑い，腹水穿刺検査を行う．腹水中の細菌証明，腹水中の多核白血球数の増加から診断する．細菌培養が陰性でも，腹水中の好中球数が500/μL以上，または好中球数が250～500/μLの場合でも自他覚症状を伴えばSBPと診断する．グラム陰性桿菌が原因であることが多い．
5）凝固障害：
肝硬変では，脾機能亢進症により血小板減少症をきたすのに加え，肝での凝固因子の合成低下により，フィブリノゲン（第Ⅰ因子），プロトロンビン（第Ⅱ因子），第Ⅴ，Ⅵ，Ⅸ，Ⅹの各因子の合成が低下する．胆汁うっ滞の合併により脂溶性のビタミンKの吸収障害が生じ，第Ⅴ因子を除く各因子がさらに減少しうる．
6）肝腎症候群（hepatorenal syndrome）：
肝硬変末期の肝不全患者においてみられる急性腎不全であり，腎臓内の血流変化により，腎皮質の血管が攣縮し，腎血流が低下し，糸球体濾過量は低下する．過剰の利尿剤投与，腹腔穿刺による腹水除去，下痢などによる血管内脱水が誘因となる．
　急激に進行するI型と難治性腹水などを伴い比較的緩除に進行するⅡ型に分けられる．
7）肝細胞癌：
【⇨9-12-1）】
経過・予後
　肝硬変の経過や予後は病因によって多様である．肝硬変の3大死因は，肝不全，消化管出血，肝細胞癌であるが，肝細胞癌による死亡の割合が増加し，肝細胞癌の合併が予後を規定する因子となっている．これは，肝不全や消化管出血に対する治療が進歩したことによるものと考えられる．
　Child-Pughスコアは，肝予備能を評価する方法であるが，予後予測にも有用で，グレードCの患者の予後はきわめて不良である．また，短期の予後予測として血清ビリルビン，クレアチニン，プロトロンビン時間を使って計算するmodel for end stage liver disease（MELD）スコアがあり，肝移植前の予後予測と肝移植の適応判定に有用である．＊肝移植のための評価（MELDスコア）MELDスコア＝3.78×log_e（T-Bil mg/dL）＋11.2×log_e（PT-INR）＋9.57×log_e（Cre mg/dL）＋6.43
治療
1）日常生活指導：
黄疸，腹水，肝性脳症がみられる非代償期には安静にする．代償期で，肝機能が安定し，破裂の危険性のある食道静脈瘤がない場合は，筋萎縮予防のため，過剰な安静は控え，むしろ軽度の運動（疲れの残らない程度）を行うことが望ましい．
2）薬物療法：
ウルソデオキシコール酸やグリチルリチン製剤などの肝庇護剤や除鉄療法（貧血がない場合）により，肝の炎症を抑制し肝機能の維持に努める．血清アルブミン値が3.5 g/dL以下の患者は，分岐鎖アミノ酸製剤の投与を考慮する．
　原因療法として，B型肝炎ウイルスによる肝硬変では抗ウイルス薬（核酸アナログ製剤）が肝病態の改善や非代償性肝硬変への進展予防のため投与される．C型肝炎ウイルスによる代償性肝硬変にはインターフェロン治療（インターフェロン単独もしくはリバビリン併用）でC型肝炎ウイルスを排除できれば，病態の改善と肝発癌抑止が期待できる．
3）食事・栄養療法：
食事はバランスがとれ，塩分控えめで食物繊維の多い食事摂取を基本とする．
　摂取カロリーは，日常生活活動強度から算出する．代償性肝硬変では，25～35 kcal/kg（標準体重）/日，蛋白質は1.0～1.3 g/kg（標準体重）/日とし，脂質摂取量は総エネルギーの20～25％にする．肝硬変患者は，早朝空腹時は飢餓状態にあり，栄養状態の悪化の原因となるため，分割食として就寝前軽食摂取（late evening snack：LES）を行う．1日摂取総カロリーから200 kcal程度を差し引き，就寝前に分岐鎖アミノ酸を豊富に含む肝不全用経口栄養剤（200 kcal程度）などを摂取する．また，肝硬変の増悪因子であるアルコールについては禁酒を指導する．肝硬変では，免疫能低下があるため，生食摂取（特に夏場の刺身など）は控えるよう指導する．これはビブリオ菌の一種，Vibrio vulnificusという菌が海水温の上昇とともに，海産物中で増殖し，健康人がこの菌に汚染されたものを食べても，下痢する程度であるが，肝硬変の患者がこのビブリオ菌に感染すると，重症となり生命の危険にかかわる可能性が高いためである．
4）腹水：合併症参照
5）肝性脳症：合併症参照
6）消化管出血：合併症参照
7）肝移植：
黄疸が進行する非代償性肝硬変では，肝移植を検討する．わが国では，脳死肝移植数はいまだ少なく，いまのところ生体肝移植が主流である．肝移植の適応時期は，MELDスコアなどの客観的な指標や臨床的評価により決定される．［坂井田　功］
■文献
Sherlock S, Dooley J；小俣政男監訳：シャーロック肝臓病学．pp315-328, 西村書店，東京，2004．

表9-5-1
肝硬変の成因">

表9-5-1

表9-5-2
Child-Pugh スコア">

表9-5-2

表9-5-3
肝硬変の症状・徴候">

表9-5-3

図9-5-1
全国集計における肝硬変の成因別頻度">

図9-5-1

図9-5-2
肝類洞の構造">

図9-5-2

出典　内科学第10版内科学第10版について　情報

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